PMID- 22223846
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20201209
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 33
IP  - 3
DP  - 2012 Mar
TI  - Hypoxia-inducible factor-1alpha inhibition by a pyrrolopyrazine metabolite of 
      oltipraz as a consequence of microRNAs 199a-5p and 20a induction.
PG  - 661-9
LID - 10.1093/carcin/bgr320 [doi]
AB  - Oltipraz, a cancer chemopreventive agent, has antitumor and antiangiogenic 
      effects. In animal models and clinical studies, a considerable amount of oltipraz 
      is metabolized to pyrrolopyrazines, including M2, 
      7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine; M3, 
      7-methyl-8-(methylsulfinyl)-6-(methylthio)pyrrolo[1,2-a]pyrazine and M4, 
      7-methyl-6,8-bis(methylsulfinyl)pyrrolo[1,2-a]pyrazine. In view of the role of 
      hypoxia-inducible factor-1 (HIF-1) alpha in tumor growth and angiogenesis, this study 
      investigated whether pyrrolopyrazine metabolites of oltipraz inhibit HIF-1alpha 
      induction, and if so, what the molecular basis is. M2 treatment inhibited the 
      induction of HIF-1alpha by a variety of stimuli including insulin, hypoxia, CoCl(2) 
      and hydrogen peroxide in HCT116 cells, whereas M3 or M4 failed to do so. 
      Consistently, M2 prevented HIF-1alpha target gene induction. Moreover, it inhibited 
      cancer cell invasion and migration. M2 caused no change in the expression of 
      HIF-1alpha transcript but increased the levels of precursor forms of microRNAs 
      (miRNAs) 199a-5p and 20a, but not those of primary forms, indicating facilitation 
      of the maturation process of the miRNAs by M2. Increased levels of the miRNAs 
      contributed to HIF-1alpha repression, as shown by the results of experiments using 
      mimics. Consistently, M2 treatment inhibited de novo synthesis of HIF-1alpha, as 
      supported by decreased incorporation of [(35)S]-methionine into HIF-1alpha with no 
      changes in its ubiquitination or degradation. 
      7-Ethyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, a synthetic analog of M2, had 
      a similar inhibitory effect. In conclusion, M2 with pyrrolopyrazine structure and 
      its 7-ethyl congenor have the ability to prevent the induction of HIF-1alpha, which 
      may result from the inhibition of HIF-1alpha de novo synthesis, as mediated by the 
      induction of miR-199a-5p and miR-20a.
FAU - Kang, Seul Gi
AU  - Kang SG
AD  - Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 
      151-742, South Korea.
FAU - Lee, Woo Hyung
AU  - Lee WH
FAU - Lee, Young Hun
AU  - Lee YH
FAU - Lee, Yong Sup
AU  - Lee YS
FAU - Kim, Sang Geon
AU  - Kim SG
LA  - eng
PT  - Journal Article
DEP - 20120104
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (7-ethyl-6,8-bis(methylthio)pyrrolo(1,2-a)pyrazine)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (MIRN20a microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Pyrazines)
RN  - 0 (Pyridazines)
RN  - 0 (Pyrroles)
RN  - 0 (Pyrrolopyridazine)
RN  - 0 (Thiones)
RN  - 0 (Thiophenes)
RN  - 0 (mirn199 microRNA, human)
RN  - 3G0H8C9362 (Cobalt)
RN  - 6N510JUL1Y (oltipraz)
RN  - 84201-40-1 (7-methyl-6,8-bis(methylthio)pyrrolo(1,2-a)pyrazine)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EVS87XF13W (cobaltous chloride)
SB  - IM
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cobalt/pharmacology
MH  - HT29 Cells
MH  - Humans
MH  - Hydrogen Peroxide/pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics/metabolism
MH  - Insulin/pharmacology
MH  - MicroRNAs/biosynthesis/*metabolism
MH  - Neoplasm Invasiveness
MH  - Neovascularization, Pathologic/genetics
MH  - Pyrazines/*metabolism/*pharmacology
MH  - Pyridazines/pharmacology
MH  - Pyrroles/*pharmacology
MH  - Thiones
MH  - Thiophenes
EDAT- 2012/01/10 06:00
MHDA- 2012/05/09 06:00
CRDT- 2012/01/07 06:00
PHST- 2012/01/07 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
AID - bgr320 [pii]
AID - 10.1093/carcin/bgr320 [doi]
PST - ppublish
SO  - Carcinogenesis. 2012 Mar;33(3):661-9. doi: 10.1093/carcin/bgr320. Epub 2012 Jan 
      4.